US6806253B2 - Immunodulatory complex and use thereof in helicobacter diseases - Google Patents

Immunodulatory complex and use thereof in helicobacter diseases Download PDF

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US6806253B2
US6806253B2 US09/125,747 US12574798A US6806253B2 US 6806253 B2 US6806253 B2 US 6806253B2 US 12574798 A US12574798 A US 12574798A US 6806253 B2 US6806253 B2 US 6806253B2
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complex
helicobacter
immunomodulatory
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complex according
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US20020032152A1 (en
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Fernand Narbey Torossian
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/105—Delta proteobacteriales, e.g. Lawsonia; Epsilon proteobacteriales, e.g. campylobacter, helicobacter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/025—Enterobacteriales, e.g. Enterobacter
    • A61K39/0266—Klebsiella
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A61K39/092—Streptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/102—Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/70—Multivalent vaccine

Definitions

  • the present invention relates to a therapeutic and preventive anti-bacterial vaccine complex which possesses a vaccinating power linked to the presence of specific antigens against Helicobacter pylori (previously called Campylobacter pylori ), Helicobacter hepaticus, Helicobacter coronari , and nonspecific antigens providing immunomodulation.
  • Helicobacter pylori previously called Campylobacter pylori
  • Helicobacter hepaticus Helicobacter coronari
  • nonspecific antigens providing immunomodulation.
  • the surface antigens of the walls, membranes or capsules are of a glycoprotein, polypeptide or polysaccharide nature.
  • Vaccines combining associative factors, such as membrane proteoglycan or polysaccharide substances, extracted from pathogenic microbes, with ribonucleic acid of ribosomal origin (RNA) can be used in the production of acellular vaccines (cf. Inf. and Immunity, 1, 574-82, 1970 and PCT WO 94/22462).
  • associative factors such as membrane proteoglycan or polysaccharide substances, extracted from pathogenic microbes
  • RNA ribonucleic acid of ribosomal origin
  • These vaccines use specific antigens corresponding to specifically determined microbial diseases.
  • RNA of the ribosomes in particular
  • ICC Immunocompetent cells
  • RNA preferably of ribosomal origin
  • an amino acid sequence of glycoprotein nature preferably present in type III collagen.
  • collagen represents approximately a third of the proteins in the body.
  • the type III was chosen for its amino acid sequence and its presence in the dermis, the vascular wall and the digestive epithelial mucous membranes.
  • cell membrane fractions derived from the same microbes as those which served for the production of the ribosomal RNA. These membrane fractions contain all of the peptidoglycan substances and are known, in addition, as immunity adjuvants.
  • glucopolysaccharide or proteoglycan membrane fractions derived from various microbial organisms which have served to provide the RNA by extraction of their ribosomes, which microbes are known for their immunogenesis (recruitment of macrophages, activation of T lymphocytes, potentiation of the synthesis of immunoglobulins, secretory IgA's in particular (11 S), increase in phagocytosis and stimulation of dependent T cells and the like).
  • the T lymphocytes act by themselves and/or through the cytokines, and either an inflammatory type response or a cytotoxic response is observed.
  • the pathogenic power of Helicobacter lies in its ability to colonize the gastric mucous membrane, to survive in the gastric juice and to multiply therein in spite of the host's immune response, and to generate lesions which are sometimes irreversible (adenocarcinoma, gastric lymphoma or MALT “mucous associated lymphoid tissue” lymphomas),
  • the complex of the invention comprises dual molecules constituted by the coupling of a functional amino acid arm, ensuring binding to a target, with a genetic RNA arm corresponding to the coded description of the composition of the functional arm.
  • RNAs of ribosomal origin which can be used may be extracted from the strains chosen from the following group, this list not being limitative:
  • Helicobacter pylori or Campylobacter
  • hepaticus coronari . . .
  • Streptococcus ( pneumoniae and pyogenes )
  • Corynebacterium granulosum, paryum, acnes
  • Mycobacterium tuberculosis, smegmatis, chelonei .
  • Nocardia asteroides, brasiliensis, rhodocrans, opaca, rubra )
  • the average molecular weights of these RNAs are between 5104 and 108 Dalton.
  • RNA precipitation is a process for extracting RNA described in Infect. and Immunity, 1. 574-82. 1970; the bacteria are ground and then subjected to fractional precipitation, the ribosomal proteins are solubilized, the RNA precipitated is treated with Pronase and, finally, purified by ion-exchange chromatography.
  • the final purification may be carried out by molecular sieve chromatography. See in particular on this subject:
  • Hemophilus influenzae capsulear polysaccharide polyribosephosphate type
  • Escherichia coil capsule polysaccharides
  • LDERITZ et al. (1977) Somatic and capsular antigens of gram-negative bacteria (Compr. Biochem. 26 A, 105-228).
  • LPS membrane lipopolysaccharides
  • Kiebsiella ( pneumoniae and rhinoscleromatis )
  • Serratia marcescens, corralina, indica, plymuthica, kiluea
  • Salmonella typhimurium Salmonella typhimurium.
  • GOBERT B.
  • LABIGNE A.
  • de KORWIN J. D.
  • CONROY M. C.
  • BENE M. C.
  • FAURE G. C.—Polymerase chain reaction for Helicobacter pylori , (Rev. Esp. Enf Digest, 1980, 78 (suppl 1), 4.
  • Streptococci, staphylococci and lactobacilli the surface of gram-positive bacteria is made of teichoic acid, which is a glycerol polymer, linked by phosphodiester bridges).
  • FISKE and SUBBAROW Assay of phosphorus. HPLC chromatography on an ion-exchange column for qualitative control (J. Biol. Chem. (1926), 66, 375).
  • the collagen type III used is characterized by the following amino acid concentrations expressed in g/kg:
  • composition of the vaccine complex which is the subject of the invention, combining ribosomal RNAs or RNA fragments, membrane fractions (for example proteoglycans from Klebsiella pneumoniae ) and collagen type III, supplemented with sodium chloride and an anti-inflammatory agent, makes it possible, by administration of low doses causing no toxicity, to obtain a high level of protection and of cure.
  • the preferred presentation is the injectable form of the composition presented above, but it is possible to use other presentations and/or other areas or additives compatible with a medical use.
  • This therapeutic (vaccine) complex may be assimilated to a specific vaccine (through an “inert system” which is intended to increase the immunogenicity of a recombinant subunit vaccine and of vaccines consisting of peptides), and a nonspecific vaccine with the characteristics of a lymphokine, which, by attaching to the macrophages, plays an essential role in the immune response towards Helicobacter (KAZI J. I., SINNIAH R., JAFFRAY N. A., ALAM S. M., ZAMAN V., ZUBERI S. J. & KAZI A. M.: Cellular and humoral immune response in Campylobacter pylori -associated chronic gastritis, J. Pathol. 159; 23 1-237, 1989).
  • VENNEMAN et al. have thought since 1972 that the real antigen could be associated with RNA, whose role could be that of an adjuvant, (Infections and Immunity, 5(3), pp. 268-282, 1972). They vaccinated mice with ribosomal RNA, extracted with phenol at 65° C. from ribosomes of a strain of Salmonella typhimurium . Thirty days after this vaccination, it was found that the animals were better protected than with an (attenuated) live strain vaccine.
  • the ribosomal RNA extracted from Streptococcus pneumoniae induces protection of a humoral nature and the ribosomal RNA extracted from Klebsiella pneumoniae induces protection of a cellular nature.
  • This mixture when injected in vivo into mice and guinea pigs, exerts an action on the alveolar macrophages.
  • This “transient” effect is determined by assaying the acid phosphatase in the direct haemolysis plaques in contact with mouse spleen cells.
  • the treatment with our therapeutic and vaccine complex is, for its part, followed by a cellular and humoral immunostimulant effect, with a significant specific and nonspecific action on Helicobacter pylori . It is the patient's own body which is stirred into action to “reject the infected cells”.
  • a cure is obtained by the action of the PMNs (Polymorphonuclear leukocytes) and of the moncytes simultaneously stirred into action.
  • This therapeutic mechanism therefore makes it possible to produce a natural cloning by virtue of the (nonspecific bacterial ribosomal) RNAs opsonized by the adjuvant developed (combination of membrane proteoglycans, of collagen type III and of sodium chloride).
  • corticoids Betamethasone type, for example
  • disodium phosphate a dose of 20 to 60 mg, by the I.V. or I.M. route.
  • This action is also accompanied by production of endogenous interferon as well as an activation of the NK cells.
  • the aim of our immunomodulatory vaccine complex is therefore to induce a local and general immune response which has the effect of preventing or at least of reducing (down to a possible self-defence threshold) the proliferation of an infectious agent introduced into the body.
  • Our therapeutic innovation consists, inter alia, in moderating or eliminating the existence of “suppressive cells” exerting a proinfectious action, in causing an anti-ulcerous reaction by a defensive cellular and/or humoral response; it is the therapeutic response to the problem detected since 1993 by Kist et al.
  • our therapeutic complex acts by directed evolution, producing RNA molecules which block the Helicobacter pylori infection and increase the immunodefence.
  • the vaccine complex may be administered orally or parenterally:
  • each day of the week of treatment comprising a slow infusion of 500 ml of a solution containing:
  • Betamethasone disodium phosphate that is to say 2 ml of injectable solution.
  • This treatment by slow I.V. infusion may be replaced by a treatment by subcutaneous injections on patients who can be followed on an ambulatory basis, each injection containing:
  • Betamethasone disodium phosphate that is to say 1 ml of injectable solution.
  • This treatment may be continued for several weeks.
  • Betamethasone disodium phosphate 2 mg.
  • This treatment can be provided at the rate of 2 tablets per day for one month, followed by booster periods of two tablets per day, one week per month for 3 months.
  • Adhesive transdermal therapeutic sytem composed of a reservoir and a permeable membrane providing continuous passage of the active ingredients across the skin and into the bloodstream at a constant rate.
  • the device should be stuck to a healthy skin surface which is dry and not very hairy (side wall of the abdomen or of the thorax for example).
  • Its content is the content of one tablet, and its dosage is identical to the oral route (at the rate of one “patch” for 2 daily tablets).
  • Mr. Robert G. 64 years old, was hospitalized following epigastralgia, pyrosis and abdominal pain associated with a transit disorder with alternating diarrhoea—constipation.
  • Digestive endoscopy showed a gastrooesophageal reflux pathology by the opening of the cardia, causing an oesophagitis and a peptic ulcer of the lower oesophagus.
  • Biopsies were performed, as well as a rapid urease test. The latter, as well as anatomopathology and culture, confirmed the presence of Helicobacter pylori.
  • the treatment with the vaccine complex which is the subject of the invention was then carried out in the form of subcutaneous injections.

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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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US09/125,747 1996-02-26 1997-02-25 Immunodulatory complex and use thereof in helicobacter diseases Expired - Lifetime US6806253B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9602445A FR2745186B1 (fr) 1996-02-26 1996-02-26 Complexe immunomodulateur et ses utilisations pour le traitement et la prevention des recidives des affections par helicobacter
FR9602445 1996-02-26
PCT/FR1997/000334 WO1997030716A1 (fr) 1996-02-26 1997-02-25 Complexe vaccinal anti-helicobacter

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US20020032152A1 US20020032152A1 (en) 2002-03-14
US6806253B2 true US6806253B2 (en) 2004-10-19

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US (1) US6806253B2 (de)
EP (1) EP0969851B1 (de)
JP (1) JP2000506831A (de)
CN (1) CN1089607C (de)
AT (1) ATE267604T1 (de)
AU (1) AU722200B2 (de)
CA (1) CA2246744C (de)
DE (1) DE69729324T2 (de)
ES (1) ES2222501T3 (de)
FR (1) FR2745186B1 (de)
WO (1) WO1997030716A1 (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6290962B1 (en) * 1992-11-03 2001-09-18 Oravax, Inc. Urease-based vaccine and treatment for helicobacter infection
US8029777B2 (en) * 2004-08-13 2011-10-04 Marshall Barry J Helicobacter system and uses thereof
CA2576280A1 (en) 2004-08-13 2006-02-16 Barry J. Marshall Helicobacter pylori-based delivery system

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4460575A (en) 1980-02-20 1984-07-17 Pierre Fabre S.A. Vaccinal complex containing a specific antigen and vaccine containing it

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2703252B1 (fr) * 1993-03-31 1996-09-06 Fernand Narbey Torossian Complexe immunomodulateur anti SIDA.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4460575A (en) 1980-02-20 1984-07-17 Pierre Fabre S.A. Vaccinal complex containing a specific antigen and vaccine containing it

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Buck et al. "Relation of Campylobacter pyloridis to Gastric and Peptic Ulcer", The Journal of Infectious Diseases, vol. 153, No. 4, pp. 664-669, 1986.* *
HP World-Wide, a publication from Brocades Pharma BV Leiderdorp, The Netherlands, Feb. 1992.* *
Rappuoli et al Development of a vaccine against Helicobacter pylori : a short overview, European Journal of Gastroenterology and Hepatology, vol. 5, (suppl. 2) pp. 576-578, 1993.* *
U.S. patent application Ser. No. 08/347,322, Torossian, filed Jan. 30, 1995.
Use of Bacterial Ribosomal Immunostimulators in Respiratory Tract.
Yokota et al. "Low Antigenicity of the Polysaccharide Region of Helicobacter pylori" Infection and Immunity vol. 65, No. 9, pp. 3509-3512, 1997.* *

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ATE267604T1 (de) 2004-06-15
CA2246744C (fr) 2011-01-04
US20020032152A1 (en) 2002-03-14
JP2000506831A (ja) 2000-06-06
AU722200B2 (en) 2000-07-27
EP0969851B1 (de) 2004-05-26
CN1211924A (zh) 1999-03-24
FR2745186B1 (fr) 1998-12-31
AU2099897A (en) 1997-09-10
DE69729324T2 (de) 2005-06-23
DE69729324D1 (de) 2004-07-01
ES2222501T3 (es) 2005-02-01
CA2246744A1 (fr) 1997-08-28
EP0969851A1 (de) 2000-01-12
CN1089607C (zh) 2002-08-28
FR2745186A1 (fr) 1997-08-29
WO1997030716A1 (fr) 1997-08-28

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